The long term objective of this project is to gain information concerning the mechanism(s) by which aluminum causes bone pathology. Elevated levels of aluminum in bone have been implicated in the etiology of several osteodystrophies in individuals with chronic renal failure. The characteristic features of these pathologies include defective bone mineralization, normal or increased osteoid, and reduced bone cell number and activity. Aluminum intoxication during embryonic and fetal development has been associated with gross skeletal abnormalities. There is no information on the cellular mechanisms by which aluminum perturbs bone formation during early development. This research will utilize long bone development in the chick embryo as an experimental model. The specific research will provide information on the relationship between aluminum toxicity and (a) osteoprogenitor cell proliferation and differentiation (Specific Aim 1), (b) osteoblast activity in extracellular matrix production (Specific Aim 2) and mineralization (Specific Aim 3), and (c) circulating levels of systemic factors (PTH, calcium, phosphorus), and local factors (bone Gla protein, alkaline phosphatase activity) regarded as regulators and/or indicators of bone formation and metabolism (Specific Aim 4). The specific aims will be accomplished by histological and histochemical investigation, histomorphometric analysis, and biochemical measurements of the long bone of chick embryos exposed to chronic aluminum intoxication. In addition to information on the possible mode of action of aluminum toxicity on bone development, the use of aluminum as a relatively specific blocker of bone formation should allow a better understanding of the regulatory processes may also be important in other diseases of the skeletal system.